Safety and efficacy of Sorbiflore®ADVANCE (Lactobacillus rhamnosus CNCM I-3698 and Lactobacillus farciminis CNCM I-3699) as a feed additive for weaned piglets.
Following a request from the European Commission, the EFSA Panel on Additives and products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of Sorbiflore® ADVANCE when used as a zootechnical feed additive for weaned piglets. Sorbiflore® ADVANCE results from the fermentation of milk based-broth with Lactobacillus rhamnosus CNCM I-3698 and Lactobacillus farciminis CNCM I-3699. The additive is intended for use in feed for weaned piglets at the minimum concentration of 1.25 × 108 viable forming units (VFU)/kg and the maximum concentration of 5 × 108 VFU/kg complete feed. The data submitted did not allow a full characterisation of the additive, and therefore, uncertainty remains on the nature of the product in terms of viability, on the ratio between the active agents and on the stability of the additive. The active agents fulfil the requirements of the qualified presumption of safety (QPS) approach to the assessment of safety and no concerns are expected from other components of the additive. Consequently, Sorbiflore® ADVANCE is presumed to be safe for the target animals, consumers of products from animals receiving the additive and the environment. The additive should be considered a respiratory sensitiser. In the absence of data, no conclusions could be drawn on the irritancy of Sorbiflore® ADVANCE to skin and eyes and on its dermal sensitisation potential. Sorbiflore® ADVANCE at 1.25 × 108 VFU/kg feed has the potential to be efficacious in weaned piglets.


Preparation and Protonation of Fe2(pdt)(CNR)6, Electron-Rich Analogues of Fe2(pdt)(CO)6.
The complexes Fe2(pdt)(CNR)6 (pdt(2-) = CH2(CH2S(-))2) were prepared by thermal substitution of the hexacarbonyl complex with the isocyanides RNC for R = C6H4-4-OMe (1), C6H4-4-Cl (2), Me (3). These complexes represent electron-rich analogues of the parent Fe2(pdt)(CO)6. Unlike most substituted derivatives of Fe2(pdt)(CO)6, these isocyanide complexes are sterically unencumbered and have the same idealized symmetry as the parent hexacarbonyl derivatives. Like the hexacarbonyls, the stereodynamics of 1-3 involve both turnstile rotation of the Fe(CNR)3 as well as the inversion of the chair conformation of the pdt ligand. Structural studies indicate that the basal isocyanide has nonlinear CNC bonds and short Fe-C distances, indicating that they engage in stronger Fe-C π-backbonding than the apical ligands. Cyclic voltammetry reveals that these new complexes are far more reducing than the hexacarbonyls, although the redox behavior is complex. Estimated reduction potentials are E1/2 ≈ -0.6 ([2](+/0)), -0.7 ([1](+/0)), and -1.25 ([3](+/0)). According to DFT calculations, the rotated isomer of 3 is only 2.2 kcal/mol higher in energy than the crystallographically observed unrotated structure. The effects of rotated versus unrotated structure and of solvent coordination (THF, MeCN) on redox potentials were assessed computationally. These factors shift the redox couple by as much as 0.25 V, usually less. Compounds 1 and 2 protonate with strong acids to give the expected μ-hydrides [H1](+) and [H2](+). In contrast, 3 protonates with [HNEt3]BAr(F)4 (pKa(MeCN) = 18.7) to give the aminocarbyne [Fe2(pdt)(CNMe)5(μ-CN(H)Me)](+) ([3H](+)). According to NMR measurements and DFT calculations, this species adopts an unsymmetrical, rotated structure. DFT calculations further indicate that the previously described carbyne complex [Fe2(SMe)2(CO)3(PMe3)2(CCF3)](+) also adopts a rotated structure with a bridging carbyne ligand. Complex [3H](+) reversibly adds MeNC to give [Fe2(pdt)(CNR)6(μ-CN(H)Me)](+) ([3H(CNMe)](+)). Near room temperature, [3H](+) isomerizes to the hydride [(μ-H)Fe2(pdt)(CNMe)6](+) ([H3](+)) via a first-order pathway.


Sexual Aging: A Systematic Review of Qualitative Research on the Sexuality and Sexual Health of Older Adults.
Negative stereotypes regarding the sex lives of older adults persist, despite sexuality being an important factor that influences the quality of life. We conducted a systematic review of the qualitative literature on the sexuality and sexual health of older adults to address which topics have been researched and the quality of research within this field. We searched PsycINFO, SocINDEX, MEDLINE, and CINAHL for qualitative articles investigating the sexuality of adults aged 60+ years. We analyzed 69 articles using thematic analysis to synthesize their findings. We identified two overarching thematic categories: psychological and relational aspects of sexuality (personal meanings and understandings of sex, couplehood aspects, and sociocultural aspects) and health and sexuality (effects of illness and/or treatment on sexuality, and help-seeking behaviors). Research is needed into male sexual desire and pleasure, culture-specific and sexual/gender identities and their effect on outcomes such as help-seeking behavior and sexual satisfaction, and sexual risk-taking in older adults.


Recent progress and challenges in the discovery of new neuraminidase inhibitors.
At present, the key public health concern is to define the way in which the next influenza pandemic should be controlled. While influenza vaccines are available, their effectiveness could be significantly reduced if new strains differ significantly from those of the vaccines. Therefore, antiviral drugs play an important role in the prevention and management of influenza. The influenza neuraminidase (NA), a surface-glycoprotein enzyme involved in releasing the virus from the host cell, has been considered as an essential therapeutic target for treatment and prophylaxis of influenza infection. It is a highly conserved feature of the active site across all influenza A and B viruses and is of particular interest because compounds NA inhibitors (NAIs) can be cross-reactive against multiple types and subtypes of influenza. Currently, there are two NAI drugs which are licensed worldwide: oseltamivir and zanamivir, and two more drugs which have received recent approval in Japan: peramivir and laninamivir. Sudden changes in NAI susceptibility have stressed the urgent need in searching for novel inhibitors. In this review, a potential pitfall in NA-based assays and the progress in the chemical synthesis of all patented NAIs from February 2006 to July 2012 are discussed. Both NA enzyme inhibition and X-ray crystallography data have suggested that the strategy of designing NAIs binding to the highly conserved region of NA can lead to inhibitors that are effective against all influenza NA subtypes. A number of new synthetic entries having unique structural frameworks that were designed based on computational study of X-ray structures of NA. They strongly exhibited the activity of NA in the low nanomolar range such as phosphonate congeners of zanamivir and oseltarmivir. Screening strategies based on the chemical diversity of natural products have revealed that flavonoids are the most prominent scaffolds possessing NA inhibitory activity. However, these substituted phenyl-benzopyrane compounds have been reported to exert a considerable quenching effect, causing false-positive results in the commonly used method of enzyme-based NA inhibition assays, and thus, reliability of the flavonoid-based NAIs reported in the literature.


Prion protein paralog doppel protein interacts with alpha-2-macroglobulin: a plausible mechanism for doppel-mediated neurodegeneration.
Doppel protein (Dpl) is a paralog of the cellular form of the prion protein (PrP(C)), together sharing common structural and biochemical properties. Unlike PrP(C), which is abundantly expressed throughout the central nervous system (CNS), Dpl protein expression is not detectable in the CNS. Interestingly, its ectopic expression in the brain elicits neurodegeneration in transgenic mice. Here, by combining native isoelectric focusing plus non-denaturing polyacrylamide gel electrophoresis and mass spectrometry analysis, we identified two Dpl binding partners: rat alpha-1-inhibitor-3 (alpha(1)I(3)) and, by sequence homology, alpha-2-macroglobulin (alpha(2)M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrP(C) with either alpha(1)I(3) or alpha(2)M. Nevertheless, enzyme-linked immunosorbent assays and surface plasmon resonance experiments revealed a high affinity binding occurring between PrP(C) and Dpl. In light of these findings, we suggest a mechanism for Dpl-induced neurodegeneration in mice expressing Dpl ectopically in the brain, linked to a withdrawal of natural inhibitors of metalloproteinase such as alpha(2)M. Interestingly, alpha(2)M has been proven to be a susceptibility factor in Alzheimer's disease, and as our findings imply, it may also play a relevant role in other neurodegenerative disorders, including prion diseases.


Uniting Drug and Delivery: Metal Oxide Hybrid Nanotherapeutics for Skin Wound Care.
Wound care and soft tissue repair have been a major human concern for millennia. Despite considerable advancements in standards of living and medical abilities, difficult-to-heal wounds remain a major burden for patients, clinicians and the healthcare system alike. Due to an aging population, the rise in chronic diseases such as vascular disease and diabetes, and the increased incidence of antibiotic resistance, the problem is set to worsen. The global wound care market is constantly evolving and expanding, and has yielded a plethora of potential solutions to treat poorly healing wounds. In ancient times, before such a market existed, metals and their ions were frequently used in wound care. In combination with plant extracts, they were used to accelerate the healing of burns, cuts and combat wounds. With the rise of organic chemistry and small molecule drugs and ointments, researchers lost their interest in inorganic materials. Only recently, the advent of nano-engineering has given us a toolbox to develop inorganic materials on a length-scale that is relevant to wound healing processes. The robustness of synthesis, as well as the stability and versatility of inorganic nanotherapeutics gives them potential advantages over small molecule drugs. Both bottom-up and top-down approaches have yielded functional inorganic nanomaterials, some of which unite the wound healing properties of two or more materials. Furthermore, these nanomaterials do not only serve as the active agent, but also as the delivery vehicle, and sometimes as a scaffold. This review article provides an overview of inorganic hybrid nanotherapeutics with promising properties for the wound care field. These therapeutics include combinations of different metals, metal oxides and metal ions. Their production, mechanism of action and applicability will be discussed in comparison to conventional wound healing products.


Integron Identification in Bacterial Genomes and Cassette Recombination Assays.
Integrons are genetic elements involved in bacterial adaptation to the environment. Sedentary chromosomal integrons (SCIs) can stockpile and rearrange a myriad of different functions encoded in gene cassettes. Through their association with transposable elements and conjugative plasmids, some SCIs have acquired mobility and are now termed Mobile Integrons (MIs). MIs have reached the hospitals and are involved in the rise and spread of antibiotic resistance genes through horizontal gene transfer among numerous bacterial species. Here we aimed at describing methods for the detection of integrons in sequenced bacterial genomes as well as for the experimental characterization of the activity of their different components: the integrase and the recombination sites.


Image-guided endoscopic surgery for spontaneous supratentorial intracerebral hematoma.
OBJECTIVE Endoscopic removal of intracerebral hematomas is becoming increasingly common, but there is no standard technique. The authors explored the use of a simple image-guided endoscopic method for removal of spontaneous supratentorial hematomas. METHODS Virtual reality technology based on a hospital picture archiving and communications systems (PACS) was used in 3D hematoma visualization and surgical planning. Augmented reality based on an Android smartphone app, Sina neurosurgical assist, allowed a projection of the hematoma to be seen on the patient's scalp to facilitate selection of the best trajectory to the center of the hematoma. A obturator and transparent sheath were used to establish a working channel, and an endoscope and a metal suction apparatus were used to remove the hematoma. RESULTS A total of 25 patients were included in the study, including 18 with putamen hemorrhages and 7 with lobar cerebral hemorrhages. Virtual reality combined with augmented reality helped in achieving the desired position with the obturator and sheath. The median time from the initial surgical incision to completion of closure was 50 minutes (range 40-70 minutes). The actual endoscopic operating time was 30 (range 15-50) minutes. The median blood loss was 80 (range 40-150) ml. No patient experienced postoperative rebleeding. The average hematoma evacuation rate was 97%. The mean (± SD) preoperative Glasgow Coma Scale (GCS) score was 6.7 ± 3.2; 1 week after hematoma evacuation the mean GCS score had improved to 11.9 ± 3.1 (p < 0.01). CONCLUSIONS Virtual reality using hospital PACS and augmented reality with a smartphone app helped precisely localize hematomas and plan the appropriate endoscopic approach. A transparent sheath helped establish a surgical channel, and an endoscope enabled observation of the hematoma's location to achieve satisfactory hematoma removal.


Convective heat transfer from a nude body under calm conditions: assessment of the effects of walking with a thermal manikin.
The present experimental work is dedicated to the analysis of the effect of walking on the thermal insulation of the air layer (I (a)) and on the convective heat transfer coefficients (h (conv)) of the human body. Beyond the standing static posture, three step rates were considered: 20, 30 and 45 steps/min. This corresponds to walking speeds of approximately 0.23, 0.34 and 0.51 m/s, respectively. The experiments took place in a climate chamber with an articulated thermal manikin with 16 independent parts. The indoor environment was controlled through the inner wall temperatures since the objective of the tests was restricted to the influence of the walking movements under calm conditions. Five set points were selected: 10, 15, 20, 25 and 30°C, and the operative temperature within the test chamber varied between 11.9 and 29.6°C. The highest and lowest I ( a ) values obtained were equal to 0.87 and 0.71 clo, respectively, and the reduction in insulation due to walking ranged between 9.8 and 11.5%. The convective coefficients (h (conv)) for the whole body and for the different body segments were also determined for each step rate. In the case of the whole body, for the standing static reference posture, the mean value of h (conv) was equal to 3.3 W/m(2)°C and a correlation [Nu = Nu(Gr)] for natural convection is also presented in good agreement with previous results. For the other postures, the values of h (conv) were equal to 3.7, 3.9 and 4.2 W/m(2)°C, respectively for 20, 30 and 45 steps/min.


Protectors of Society: Understanding the Impact of Courtesy Stigma on the Experiences of Volunteers Working With Individuals Convicted of Sexual Offences.
Volunteers are integral to the criminal justice system. For some, this involves providing support in the community to those convicted of sexual offences, which has been found to reduce the risk of reoffending. Currently, the impact on volunteers of working within this context is not well understood, despite the significant stigmatisation of those convicted of sexual offences. This study aimed to address this gap through Interpretative Phenomenological Analysis, focusing on how 'courtesy stigma' (Goffman, 1968), a type of stigma-by-association, impacted on this experience. Eleven volunteers within one organisation were interviewed. Volunteers strongly identified with the volunteer role, and stigma served to strengthen their role identity as individuals who helped those no-one else would help. Participants also exhibited some maladaptive coping strategies and symptoms indicative of burnout. These results contribute significantly to the small body of work on volunteer role identity, stigmatisation, and the social and psychological impacts of volunteer association with a highly stigmatised population.


Validation study of an end-of-life questionnaire from the Swedish Register of Palliative Care.
Quality in health care is important to measure and palliative care is no exception. The Swedish Register of Palliative Care (SRPC) is a national quality register that focuses on the last week of life. It collects data with an end-of-life questionnaire (ELQ), which is validated in this study. This study included 169 consecutive patients who had died at a palliative unit. That unit had developed a computerized end-of-life medical record module that enabled a comparison between reported data and medical records, illustrating the validity of the registry questionnaire. The paper versions of the ELQs filled in at the unit were also inspected to determine the extent of registration mistakes when completing the web questionnaire. Data from the medical records and data from the ELQs reported to the SRPC showed a congruity of 22 to 100%. A working limit of acceptable congruity was set to 80%. Eight questions fell below that line. Some of these differences were caused by systematic errors. The paper versions filled in at the unit and the data from the ELQs reported to the SRPC had a congruity of between 96% and 100%, with the exception of one question about pain evaluation, which had 91% congruity. The results in this study will be used to improve and further develop the register. Some questions need to be more specific to promote more valid registrations. Consensus on quality issues in end-of-life care would simplify the work of writing and answering the questionnaire. It is desirable to perform a similar study at hospital wards that do not specialize in palliative care; however, the anticipated lack of palliative documentation could make such a study difficult to perform.


Supraorbital endoscopic approach to colloid cysts.
Surgical approaches to colloid cysts of the third ventricle have evolved over time. In recent years, endoscopy has been recognized as an effective alternative to open surgery. The disadvantage of endoscopic treatment is the difficulty in controlling the adhesion of the cyst to the roof of the third ventricle and in obtaining complete removal of the cyst. To design and carry out a supraorbital approach to obtain a better viewing angle of the cyst and better control of the adhesion of the cyst to the roof of the third ventricle. From September 2005 to February 2008, we operated on 7 consecutive patients with colloid cysts in the third ventricle. All procedures were performed with the endoscopic supraorbital approach. The endoscopic procedure was performed with a rigid STORZ endoscope with 3 working channels. In 4 patients, the surgical supraorbital trajectory was planned with the help of a navigator. The procedures lasted between 60 and 110 minutes, including the registration on the navigation system. Near-total removal of the cyst was achieved in 6 patients. All patients were discharged within 6 days. Endoscopic treatment may be an effective and safe alternative to open surgical craniotomy. Our series shows that the endoscopic supraorbital endoscopic resection is a valuable approach to colloid cysts of the third ventricle.


Brain atrophy: an in-vivo measure of disease activity in multiple sclerosis.
Multiple sclerosis (MS) has traditionally been considered to be primarily an inflammatory demyelinating disorder. Nowadays it is recognised as both an inflammatory and a neurodegenerative condition. This recognition is reflected in the development of new disease-modifying therapies that may offer the potential to reduce axon damage, either by inhibiting neurodegeneration or by promoting endogenous repair mechanisms. Since there is only a limited correlation between the clinical features of MS and findings on conventional magnetic resonance imaging (MRI), for the evaluation of such therapies new outcome measures are warranted. Grey matter atrophy occurs in the earliest stages of MS, progresses faster than in healthy individuals, and shows significant correlations with MRI lesion load, cognitive function and measures of physical disability; indeed, brain atrophy is the best predictor of subsequent disability and can be readily measured using MRI. Furthermore, it is becoming clear that currently available therapies differ in their effects on brain atrophy, and this may have important implications for the management of MS. New MRI techniques and advances in software development offer an opportunity to extend brain atrophy measurements beyond research studies to the routine management of MS patients.


Systematic Review of Kingella kingae Musculoskeletal Infection in Children: Epidemiology, Impact and Management Strategies.
Kingella kingae, a pathogen often responsible for musculoskeletal infections in children is the most common cause of septic arthritis and osteomyelitis in children 6 to 36 months of age. The aim of this study was to perform a systematic review of previous studies to determine the proportion of K. kingae in bacteriologically proven musculoskeletal infections among the pediatric population. A secondary objective was to describe the diagnostic strategies and outcome of patients with musculoskeletal infections caused by K. kingae. A systematic review was conducted to identify publications that report on musculoskeletal infections caused by K. kingae in the pediatric population (patients 0 to <18 years old with microbiologic culture and/or polymerase chain reaction (PCR) confirmation of K. kingae and a description of the musculoskeletal infection involved). Of 144 studies included in this review, we sought to determine the proportion of K. kingae pediatric musculoskeletal infections. A total of 711 (30.8%) out of 2308 pediatric cases with culture and/or PCR proven musculoskeletal infections had K. kingae successfully identified from twenty-nine studies. Of the 1070 patients who were aged less than 48 months, K. kingae was the organism identified in 47.6% of infections. We found the average age from the collated studies to be 17.73 months. Of 520 pediatric musculoskeletal patients in which K. kingae infections were identified and where the studies reported the sites of infection, a large proportion of cases (65%) were joint infections. This was followed by 18.4% osteoarticular infection (concomitant bone and joint involvement), with isolated bone and spine at 11.9% and 3.5%, respectively. Twenty-one papers reported clinical and laboratory findings in children with confirmed K. kingae infection. The median temperature reported at admission was 37.9°C and mean was 38.2°C. Fourteen studies reported on impact and treatment, with the majority of children experiencing good clinical outcome and function following antibiotic treatment with no serious orthopaedic sequelae.


Diffusion tensor imaging in male premutation carriers of the fragile X mental retardation gene.
Older male premutation carriers of the FMR1 gene are associated with the risk of developing a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome. Although previous postmortem and in vivo magnetic resonance imaging studies have indicated white matter pathology, the regional selectivity of abnormalities, as well as their relationship with molecular variables of the FMR1 gene, has not been investigated. In this study, we used diffusion tensor imaging to study male premutation carriers with and without fragile X-associated tremor/ataxia syndrome and healthy sex-matched controls. We performed a tract of interest analysis for fractional anisotropy and axial and radial diffusivities of major white matter tracts in the cerebellar-brain stem and limbic systems. Compared with healthy controls, patients with fragile X-associated tremor/ataxia syndrome showed significant reductions of fractional anisotropy in multiple white matter tracts, including the middle cerebellar peduncle, superior cerebellar peduncle, cerebral peduncle, and the fornix and stria terminalis. Significant reduction of fractional anisotropy in these tracts was confirmed by voxel-wise analysis using tract-based spatial statistics. Analysis of axial and radial diffusivities showed significant elevation of these measures in middle cerebellar peduncle, even among premutation carriers without fragile X-associated tremor/ataxia syndrome. Furthermore, regression analyses demonstrated a clear inverted U-shaped relationship between CGG-repeat size and axial and radial diffusivities in middle cerebellar peduncle. These results provide new evidence from diffusion tensor imaging for white matter abnormalities in the cerebellar-brain stem and limbic systems among individuals with the fragile X premutation and suggest the involvement of molecular mechanisms related to the FMR1 gene in their white matter pathology.


Effect of intensive multifactorial treatment compared with routine care on aortic stiffness and central blood pressure among individuals with screen-detected type 2 diabetes: the ADDITION-Denmark study.
Diabetes is associated with increased brachial and central blood pressure and aortic stiffness. We examined the effect of intensive multifactorial treatment in general practice on indices of peripheral and central hemodynamics among patients with screen-detected diabetes. As part of a population-based screening and intervention study in general practice, 1,533 Danes aged 40-69 years were clinically diagnosed with screen-detected diabetes. General practitioners were randomized to provide intensive multifactorial treatment or routine care. After a mean follow-up of 6.2 years, an unselected subsample of 456 patients underwent central hemodynamic assessments by applanation tonometry. Central pressure was derived from the radial pulse wave. Aortic stiffness was assessed as carotid-femoral pulse wave velocity (aPWV). The intervention effect on each index of central hemodynamics was analyzed by mixed-effects models adjusted for heart rate, cluster randomization, age, and sex. At screening, median age was 59.2 years (interquartile range 55.2-64.6); 289 patients (63%) were in the intensive treatment group, and 278 patients (61%) were men. Patients in the intensive treatment group had a 0.51 m/s (95% CI -0.96 to -0.05, P = 0.03) lower aPWV compared with routine care. Respective differences for central augmentation index (-0.84% [-2.54 to 0.86]), pulse pressure (0.28 mmHg [-1.75 to 2.32]), and systolic (-1.42 mmHg [-4.47 to 1.64]) and diastolic (-1.79 mmHg [-3.72 to 0.14]) blood pressure were not statistically significant. Intensive multifactorial treatment of screen-detected diabetes during 6 years in general practice has a significant impact on aortic stiffness, whereas the effects on other hemodynamic measures are smaller and not statistically significant.


Global metabolic consequences of the chromogranin A-null model of hypertension: transcriptomic detection, pathway identification, and experimental verification.
Chromogranin A (CHGA) has a crucial role in formation of regulated secretory granules in neuroendocrine tissues and is also a prohormone that is proteolytically processed into peptides with diverse and complex actions. CHGA and several of its peptide products, including catestatin and pancreastatin, are implicated in pathogenesis of essential hypertension, insulin resistance, and the metabolic syndrome. The Chga knockout mouse (Chga KO) displays severe hypertension coupled with reduction in size, number, and density of regulated secretory granules. We performed genome-wide transcriptome profiling in Chga KO adrenal gland and liver for insight into biochemical and physiological systems altered in this monogenic mouse model of hypertension. Adrenal gene expression pathway prediction of enhanced insulin sensitivity (P = 0.03) in Chga KO was confirmed with glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) measurements: blood glucose was normal in Chga KO, blood insulin was reduced 4.5-fold (P < 0.0001), and HOMA-IR was decreased 3.8-fold (P < 0.002). Remarkably, such observations conclusively dissociate fundamental features of the metabolic syndrome in this monogenic hypertension model. Exogenous pancreastatin treatment restored insulin sensitivity in the Chga KO to near-normal levels. Gene expression predictions of decreased adrenal cholesterol biosynthesis (P < 0.001) and increased hepatic cholesterol biosynthesis (P < 0.001) were verified with tissue total cholesterol assays: Chga KO adrenal cholesterol decreased 1.8-fold (P = 0.039) and hepatic cholesterol increased 1.8-fold (P = 0.018). Transcriptional regulatory network prediction identified sets of transcription factors that may provide insight into the unclear mechanistic links among CHGA, cholesterol, insulin sensitivity, and the metabolic syndrome. These experiments demonstrate, for the first time, that genetic variation at the CHGA locus impacts insulin sensitivity and tissue cholesterol levels in an intact, living organism. The Chga KO may constitute a unique model for studying the relationship between the CHGA locus and disease phenotypes of the metabolic syndrome.


Gene-by-age effects on BMI from birth to adulthood: the Fels Longitudinal Study.
Genome wide association studies have shown 32 loci to influence BMI in European-American adults but replication in other studies is inconsistent and may be attributed to gene-by-age effects. The aims of this study were to determine if the influence of the summed risk score of these 32 loci (GRS) on BMI differed across age from birth to 40 years, and to determine if additive genetic effects other than those in the GRS differed by age. Serial measures of BMI were calculated at 0, 1, 3, 6, 9, 12, 18, and 28 months, and 4, 7, 11, 15, 19, 23, 30, and 40 years for 1,176 (605 females, 571 males) European-American participants in the Fels Longitudinal Study. SOLAR was used for genetic analyses. GRS was significant (P < 0.05) at ages: 6, 9 months, 4-15 years, and 23-40 years. Remaining additive genetic effects independently influenced BMI (P < 5.3 × 10(-5) , 0.40 < h(2) < 0.76). Some genetic correlations between ages were not significant. Differential GRS effects did not retain significance after multiple comparisons adjustments. While well-known BMI variants do not appear to have significant differential effects, other additive genes differ over the lifespan.


Sclerosing polycystic adenosis of the parotid gland: report of one case diagnosed by fine-needle cytology with in situ malignant transformation.
Sclerosing polycystic adenosis (SPA) is a rare pathological condition affecting the salivary glands, first described by Smith etal. in 1996. Even though this lesion is being increasingly diagnosed, less than 50 cases have been published in the world literature to date. In line with numerous other pathological analogies between breast and salivary gland lesions, SPA shares with fibrocystic disease of the breast many histopathological features, i.e., fibrosis, oncocytic (apocrine) changes, hyperplasia of ductal and acinar epithelium, cystic dilation of ducts, and, often, atypical epithelial changes. Most of the described cases have followed a benign clinical course, despite the frequent possibility of atypical hyperplasia in more than 50% of the cases and of the more than occasional in situ malignant transformation. In this article, we introduce a new case occurring in the parotid gland of a 57-year-old male showing atypical epithelial hyperplasia and low-grade in situ mucoepidermoid carcinoma. Fine-needle cytology (FNC) was performed on the lesion and, when a diagnosis of SPA was prospected, the variegated cytological features of the obtained sample posed several differential diagnostic problems. The spectrum of pathological lesions entering differential diagnosis comprised sebaceous adenoma, Warthin's tumors with presence of sebaceous remnants, and low-grade mucoepidermoid carcinoma. Histopathological examination disclosed SCA with intraductal neoplastic transformation resembling noninvasive low-grade mucoepidermoid carcinoma. The cytological diagnosis of SPA should be entertained whenever a polymorphous picture is found on FNC samples comprising oncocytic/apocrine changes, sebaceous cells, cystic background, and epithelial hyperplasia with low-grade cytological atypias.


Does treatment of Helicobacter pylori with antibiotics alone heal duodenal ulcer? A randomised double blind placebo controlled study.
Treatment of Helicobacter pylori infection prevents duodenal ulcer relapse. It has not been established if treatment of the infection heals duodenal ulcer. To test the hypothesis that treatment of the infection was associated with healing of duodenal ulcer. A randomised, double blind placebo controlled trial was performed to study the efficacy of an antibiotic only regimen consisting of 300 mg metronidazole, 500 mg amoxycillin, and 250 mg clarithromycin, each given four times daily for two weeks, in the healing of duodenal ulcer as assessed by endoscopy. Symptoms were controlled with acetaminophen and antacids. Of 100 consecutive patients with endoscopically established duodenal ulcer, 97 with positive rapid urease test on antral biopsy specimens were admitted into the study and 81 completed the trial. Of these, 40 were randomised to receive antibiotics and 41 to receive placebo. Treatment with antibiotics resulted in 92.5% (95% confidence interval (95% CI) 84.3-100) healing at four weeks and 100% at eight and 12 weeks; the corresponding healing rates for placebo treatment were respectively, 36.6%, 61%, and 63.4% (95% CIs 21.8-51.3, 46.0-75.9, and 48.7-78.2 respectively). The differences between the two treatment groups were significant at p < 0.001 at each time point and by life table analysis. Clearance of H pylori as assessed by urease test on antral biopsy specimens at four weeks and eradication of the organism as determined by 13C-urea breath test at eight weeks were achieved in 85% and 62.5% of patients respectively. Duodenal ulcer healed at four weeks in 87.2% and 86.2% (95% CIs 76.7-97.7 and 73.7-98.8) of patients in whom H pylori clearance or eradication, was achieved, versus 42.9% and 51.9% (95% CIs 27.9-57.8 and 38.3-65.5; p < 0.001 and < 0.003 respectively) in whom these processes failed. Stepwise discriminant analysis on 32 clinical, personal, and endoscopic characteristics as well as H pylori clearance and eradication identified H pylori clearance as the most discriminative variable for the healing of duodenal ulcer at four weeks, followed by ulcer depth and eradication of the organism. Treatment with an antibiotic only regimen was effective for the healing of duodenal ulcer, and clearance as well as eradication of H pylori contributed significantly to the healing. The results constituted the strongest evidence to date that H pylori infection was aetiologically related to duodenal ulceration, and support the concept of treating duodenal ulcer associated with H pylori as an infection and relieving its symptoms with acid reducing agents such as antacids.


Ultrasound Imaging of the Paraspinal Muscles for Interscapular Pain After Back Massage.
Muscle injuries are very common in sports medicine, but involvement of the paraspinal muscles is relatively rare. The diagnosis is usually clinical, but diagnostic imaging modalities (ie, ultrasound and magnetic resonance) identify, in detail, the anatomical site and extension of the lesion helping the physician plan a specific rehabilitation program. Likewise, the authors present an unusual case of a amateur volleyball player who suffered injury of the paraspinal muscles after a session of manual therapy with deep massage. The authors also highlight the potential role of ultrasound imaging in detecting muscle injuries not only in the limbs but also at the level of paraspinal region for prompt management and return to play.


Comparison of spot esculin hydrolysis with the PathoTec strip test for rapid differentiation of anaerobic bacteria.
The ability of several anaerobic bacteria to hydrolyze esculin to esculetin is used by clinical microbiologists and taxonomists in the differentiation and identification of both gram-positive and gram-negative microorganisms. Conventional methods used for determining esculin hydrolysis by anaerobic bacteria require 24 to 48 h for completion. In this paper we evaluate two procedures which yield rapid results. A total of 738 anaerobic bacteria were used in this study. A total of 99% of the esculin-hydrolyzing anaerobic bacteria gave positive results with the spot test in 1 h, whereas the other test method, the PathoTec strip test (General Diagnostics, Morris Plains, N.J.), required 4 h for 96% of the strains tested to yield positive reactions. Both tests showed a 100% specificity when compared with the standard broth test and are easy to perform, accurate, and economical. The spot test is superior to the PathoTec strip test in yielding results more rapidly.


Are infant-toddler social-emotional and behavioral problems transient?
To examine the persistence of parent-reported social-emotional and behavioral problems in infants and toddlers. The sample comprised 1,082 children ascertained from birth records. Children were 12 to 40 months old in year 1 (1998-1999) and 23 to 48 months old in year 2 (1999-2000). Eighty percent participated in year 1 and 91% were retained in year 2. Social-emotional and behavioral problems were measured by high scores (> or=90th percentile) on the Internalizing, Externalizing, and/or Dysregulation domains of the Infant-Toddler Social and Emotional Assessment (ITSEA). Parents reported on sociodemographic factors, family life impairment, parenting stress, and family functioning. Among children with any high ITSEA domain score in year 1, 49.9% had persistent psychopathology, as indicated by the continued presence of a high score in year 2. In multivariate analyses, persistence was significantly more likely when parents reported co-occurring problems (i.e., problems in multiple ITSEA domains), high family life disruption, and high parenting distress in year 1. Homotypic persistence rates (i.e., same domain persistence) ranged from 38% to 50%. Only for dysregulation was homotypic persistence greater when co-occurring problems were present than for dysregulation alone. Persistence patterns were similar for boys and girls. Findings indicate that infant-toddler social-emotional/behavioral problems are not transient and highlight the need for early identification, multidomain and family assessment, and effective early intervention.


Analysing management policies for operating room planning using simulation.
In this paper we analyse the operating room planning at a department of orthopaedic surgery in Sweden. We focus on the problem of meeting the uncertainty in demand of patient arrival and surgery duration and at the same time maximizing the utilization of operating room (OR) time. With a discrete-event model we simulate how different management polices affect different performance metrics such as patient waiting time, cancellations and the utilization of OR time. The experiments show that the performance of the operating room department can be improved significantly by applying a different policy in reserving OR-capacity for emergency cases together with a policy to increase staff in stand-by. Moreover, the developed simulation model provides estimates for a what-if situation related to the prognosis of an increasing number of hip-joint replacements.


Development of an ambulatory geriatrics knowledge examination for internal medicine residents.
The number of older adults needing primary care exceeds the capacity of trained geriatricians to accommodate them. All physicians should have basic knowledge of optimal outpatient care of older adults to enhance the capacity of the system to serve this patient group. To date, there is no knowledge-assessment tool that focuses specifically on geriatric ambulatory care. We developed an examination to assess internal medicine residents' knowledge of ambulatory geriatrics. A consensus panel developed a 30-question examination based on topics in the American Board of Internal Medicine (ABIM) Certification Examination Blueprint, the ABIM in-training examinations, and the American Geriatrics Society Goals and Objectives. Questions were reviewed, edited, and then administered to medical students, internal medicine residents, primary care providers, and geriatricians. Ninety-eight individuals (20 fourth-year medical students, 57 internal medicine residents, 11 primary care faculty members, and 10 geriatrics fellowship-trained physicians) took the examination. Based on psychometric analysis of the results, 5 questions were deleted because of poor discriminatory power. The Cronbach α coefficient of the remaining 25 questions was 0.48; however, assessment of interitem consistency may not be an appropriate measure, given the variety of clinical topics on which questions were based. Scores increased with higher levels of training in geriatrics (P < .001). Our preliminary study suggests that the examination we developed is a reasonably valid method to assess knowledge of ambulatory geriatric care and may be useful in assessing residents.


Atopy as a risk factor for subclinical hypothyroidism development in children.
Increased thyroid stimulating hormone (TSH) serum concentration can be a marker of subclinical hypothyroidism (SCH) or transient hyperthyrotropinemia. The aim of our study was to evaluate whether high serum TSH concentrations in allergic children could represent true SCH or isolated and transient hyperthyrotropinemia. We enrolled 620 allergic children (1.11-12.8 years) consecutively attending to our department. They were classified as atopics and non-atopics on the basis of the atopy work-up and, at baseline, they were investigated for thyroid function and low-grade inflammation state. Further, TSH was evaluated after 6 (T1) and 12 (T2) months. Both atopics and non-atopics showed higher SCH prevalence compared to controls (p=0.0055 and p=0.02, respectively), and a significant association between atopy and SCH (OR 10.11, 95% CI 1.36-75.12) was found. Both at T1 and T2, atopics had a significant risk of developing severe SCH compared to non-atopics (RR 1.8, 95% CI 1.39-2.34 and 1.61, 95% CI 1.21-2.14; respectively). Our data may suggest that hyperthyrotropinemia in atopic children could be used as a marker of true SCH.


Pulmonary Strongyloidiasis: The Varied Clinical Presentations.
Strongyloides stercoralis is a unique parasite. It can complete its life cycle entirely within the human host. As a result, an autoinfection cycle is set up. As long as there is an intact immune system, the host can control the parasitic burden, and the organism may persist for years after the initial inoculum. Most infected individuals experience mild gastrointestinal or pulmonary symptoms that may fluctuate for years. When cell-mediated immunity becomes impaired (ie, corticosteroid use, malignancy, acquired immunodeficiency syndrome), the parasite burden will grow, disseminate, and cause hyperinfection. Strongyloidiasis is endemic in the tropical and subtropical areas of the world; additionally, it is also endemic in the southeastern United States. Strongyloidiasis is associated with asthma, preexisting lung disease, and immunosuppression, including acquired immunodeficiency syndrome. Eosinophilia is not a prerequisite; therefore, the diagnosis of strongyloidiasis requires a high index of suspicion.


Outcome of cochlear implantation in pediatric auditory neuropathy.
Auditory neuropathy, characterized by absence or abnormality of auditory brainstem responses and normal otoacoustic emissions, is often associated with particularly poor response to amplification. Outcome data from four such pediatric patients who received cochlear implants are discussed. Four patients from the Carolina Children's Communicative Disorders Program were identified as having received a diagnosis of auditory neuropathy before implantation with a Clarion cochlear implant. Speech data collected after implantation were compared with data from control pediatric implant patients, matched for age at implantation and duration of implant use. Electrically evoked auditory brainstem response data and electrically evoked acoustic reflex data were also obtained. Routine clinical procedures were used to obtain speech outcome data. A 75-micros biphasic 21.1-Hz pulse train served as the eliciting stimulus for both evoked auditory brainstem responses and reflex measures, which were obtained contralateral to the implant. Speech data were comparable with those obtained from the general population of pediatric patients receiving cochlear implants at this center. Identifiable evoked auditory brainstem response data were obtained in all subjects on at least two of the three electrodes tested, and variability was comparable with that observed in other children with implants. A robust electrically evoked acoustic reflex with no decay was observed at estimated M-level in all children. The data gathered to date suggest that the outcome of cochlear implantation in these four patients is not significantly different from that in other pediatric implant patients. Physiologic data suggest that the implant was able to overcome the desynchronization hypothesized to underlie auditory neuropathy.


Mitochondrial tRNA 3' end metabolism and human disease.
Over 150 mutations in the mitochondrial genome have been shown to be associated with human disease. Remarkably, two-thirds of them are found in tRNA genes, which constitute only one-tenth of the mitochondrial genome. A total of 22 tRNAs punctuate the genome and are produced together with 11 mRNAs and 2 rRNAs from long polycistronic primary transcripts with almost no spacers. Pre-tRNAs thus require precise endonucleolytic excision. Furthermore, the CCA triplet which forms the 3' end of all tRNAs is not encoded, but must be synthesized by the CCA-adding enzyme after 3' end cleavage. Amino acid attachment to the CCA of mature tRNA is performed by aminoacyl-tRNA synthetases, which, like the preceding processing enzymes, are nuclear-encoded and imported into mitochondria. Here, we critically review the effectiveness and reliability of evidence obtained from reactions with in vitro transcripts that pathogenesis-associated mutant mitochondrial tRNAs can lead to deficiencies in tRNA 3' end metabolism (3' end cleavage, CCA addition and aminoacylation) toward an understanding of molecular mechanisms underlying human tRNA disorders. These defects probably contribute, individually and cumulatively, to the progression of human mitochondrial diseases.


Development, maturation, and necessity of transcription factors in the mouse suprachiasmatic nucleus.
The suprachiasmatic nucleus (SCN) of the hypothalamus is the master mammalian circadian clock. The SCN is highly specialized because it is responsible for generating a near 24 h rhythm, integrating external cues, and translating the rhythm throughout the body. Currently, our understanding of the developmental origin and genetic program involved in the proper specification and maturation of the SCN is limited. Herein, we provide a detailed analysis of transcription factor (TF) and developmental-gene expression in the SCN from neurogenesis to adulthood in mice (Mus musculus). TF expression within the postmitotic SCN was not static but rather showed specific temporal and spatial changes during prenatal and postnatal development. In addition, we found both global and regional patterns of TF expression extending into the adult. We found that the SCN is derived from a distinct region of the neuroepithelium expressing a combination of developmental genes: Six3, Six6, Fzd5, and transient Rx, allowing us to pinpoint the origin of this region within the broader developing telencephalon/diencephalon. We tested the necessity of two TFs in SCN development, RORα and Six3, which were expressed during SCN development, persisted into adulthood, and showed diurnal rhythmicity. Loss of RORα function had no effect on SCN peptide expression or localization. In marked contrast, the conditional deletion of Six3 from early neural progenitors completely eliminated the formation of the SCN. Our results provide the first description of the involvement of TFs in the specification and maturation of a neural population necessary for circadian behavior.


Influence of H2S and thiols on the binding of alkenes and alkynes to ReS4-: the spectator sulfido effect.
The three-component reaction of ReS4- (1), H2S, and unsaturated substrates (un = alkene, alkyne) affords the ReV derivatives Re(S)(S2un)(SH)2-. These adducts arise via the addition of H2S to intermediate dithiolates ReS2(S2C2R4)- and dithiolenes ReS2(S2C2R2)-. The species [ReS[S2C2(tms)2](SH)2]-, [ReS(S2C7H10)(SH)2]- (3), and [ReS(S2C2H4)(SH)2]- are prepared according to this route. Similarly, the selenolate-thiolate complex [ReS(S2C7H10)(SeH)(SH)]- (5) is produced by the reaction of [ReS2(S2C7H10)]- with H2Se. The corresponding reactions using benzenethiol in place of H2S afford the more thermally robust adducts [ReS[S2C2(tms)2](SH)(SPh)]-, [ReS(S2C7H10)(SH)(SPh)]- (7), and [ReS(S2C2H4)(SH)(SPh)]-. Norbornanedithiolato compounds 3, 5, and 7 are obtained as pairs of isomers that differ in terms of the relative orientation of the norbornane bridgehead relative to the Re=S unit. The reaction of [ReS(S2C7H10)(SD)2]- (3-d2) with H2S to give 3 is proposed to proceed via elimination of D2S and subsequent addition of H2S. Variable-temperature 1H NMR measurements on the equilibrium of [ReS(S2C6H12)(SPh)(SH)]- with 1,1-hexene, and PhSH gave the following results: deltaH = -7 (+/- 1) kJ x mol(-1); deltaS = 23 (+/- 4) J x mol(-1) x K(-1). Solutions of ethanedithiol and 1 react with C2(tms)2 and C2H4 to give [ReS[S2C2(tms)2](S2C2H4)]- and [ReS(S2C2H4)2]-, respectively, concomitant with loss of H2S. The pathway for the ethanedithiol reaction is examined using 2-mercaptoethanol, affording [ReS[S2C2(tms)2](SC2H4OH)]-, which does not cyclize. Treatment of a solution of diphenylbutadiyne and 1 with PhSH gives two isomers of the dithiolene [ReS(SH)(SPh)[S2C2Ph(C2Ph)]]-. The corresponding reaction of ethanedithiol, diphenylbutadiyne, and 1 affords the 1,4-diphenylbutadiene-1,2,3,4-tetrathiolate complex [[ReS(S2C2H4)]2(S4C4Ph2)]2-.


Longitudinal study of visual discomfort symptoms in college students.
To determine the variation of visual discomfort symptom reporting in a group of college students over a 1 year period. Subjects were screened for visual acuity and uncorrected refractive error before participating in the study. A survey of visual discomfort developed by Conlon et al., Vis Cogn 1999;6:637-666, and the Convergence Insufficiency Symptom Survey (CISS) were administered to a group of 23 college students twice with approximately 1 year between administrations. All subjects also completed two clinical assessments of accommodation and vergence. The mean time between administrations of the symptom surveys was 13 months. There was no clinically significant mean difference between the first and second administration of both visual discomfort surveys. The intraclass correlation coefficient was 0.82 for the Conlon et al., Vis Cogn 1999;6:637-666 survey and 0.85 for the CISS. The 95% limits of agreement for the Conlon et al., Vis Cogn 1999;6:637-666 survey was -18.44, 17.92 and for the CISS was -14.36, 13.36. The intraclass correlation coefficient values for the optometric tests ranged from 0.38 to 0.83. Visual discomfort symptoms were found to be stable in the majority of young college students over a 1 year period. However, a minority of students showed large variability between the two administrations of the surveys.


Opinions of the ePortfolio and workplace-based assessments: a survey of core medical trainees and their supervisors.
Since the introduction of Modernising Medical Careers in 2005, the electronic portfolio (ePortfolio) and workplace based assessments (WPBAs) have become integral, yet anecdotally controversial, components of postgraduate medical training. In this multi-centre, survey-based study, we looked at core medical trainees and trainers in the Northwest London region and their opinions of the ePortfolio and WPBAs. Our results demonstrate mixed feelings regarding these tools, with 60% of trainees stating that their training had not benefited from the use of an ePortfolio. 53% of trainers felt that feedback sessions with their trainees were useful; however 70% of them cited difficulties in fitting the required number of assessments within their clinical schedule. Overall, if implemented correctly, the ePortfolio and WPBAs are potentially powerful tools in the education and development of trainee doctors. However, improvements in mentoring and feedback may be needed to experience the full benefits of this system.


[Clinical study on external ear reconstruction using expanded postauricular flap and medpor framework].
To explore the feasibility of applying porous high density polyethylene (Medpor) as framework for auricle reconstruction of congenital or acquired auricular defects. From February 1999 to February 2004, 61 patients suffering from congenital or acquired auricular defects underwent auricle reconstruction with Medpor framework after expanding postauricular skin. Among them, there were 38 males and 23 females, aging from 5 to 61 years. In 40 cases of congenital microtia, two sides were involved in 1 case and one side in 39 cases. In 21 cases of traumatic auricle damage, two sides were involved in 6 cases and one side in 15 cases. The operation was performed by two stages. First stage: the expander was implanted underneath postauricular skin or soft tissue such as notrophic scar tissue for the traumatic auricle defect. Second stage:the expander was removed and auricle reconstruction was performed by placing Medpor framework between the expanded skin/scar flap and the underlying fascial flap. Sixty-one patients obtained successfully reconstructed auricles. During a follow-up of 6 months to 5 years and 1 month (mean 2.8 years), the results were excellent and good in 49 cases (80.3%), fair in 7 cases (11.5%) and poor in 3 cases (4.9%), 2 cases (3.3%) underwent replacement of Medpor framework with autogenous costal cartilage after 6 months of operation. Medpor framework would be applied safely, simply and reliably in condition that auricular framework is unfit or reluctant to undergo auricle reconstruction by using autogenous costal cartilage.


[The Stasi persecution syndrome].
For many years western psychiatrists only out of their clinical experience have known about a syndrome for which the name Stasi-persecution-syndrome will be used here. Stasi was the all powerful secret police of what was the East German Democratic Republic. The syndrome concerns an hitherto unknown number of the aprox. 50,000 survivors. It is a sequel of a form of persecution now more generally named torture. The characteristics of the persecution include arrestion, interrogations, degradation, humiliation, maltreatment, assault, mass detention in tiny rooms, hunger, cold, discrimination, defamation, disgrace, outlaw, social degradation, absence of rights, uncertainty of future, life threatening, and stigmatizing. The sequels resemble in many aspects of what is known by the psychiatry of the persecuted, but own a special flavor. Among the sequels are persisting and paranoid anxieties, re-arousable by specific situations. There are also realistic anxiety and persecution dreams, mood disturbances, lack of confidence, attempted suicide and complaints about lack of understanding by others, which the victims suffer from. Questions of indemnification for psychiatric sequelae have entered into a new stage after the East-German parliament had passed a rehabilitation bill and because of corresponding declarations in the unification treaty. Psychiatrists should fight for treatment costs and appropriate compensation for physical and psychiatric sequels of Stasi persecution to be set into reality as soon as possible. There is urgent need for a not yet existing scientific literature and publications of clinical experiences.


[Dose-response relationship between smoking status and carotid atherosclerosis].
To examine the dose-response relationship of smoking status with carotid atherosclerosis in 959 relatively healthy Chinese men. 959 older Chinese men were selected from Guangzhou Biobank Cohort Study (GBCS) on cardiovascular disease. Personal histories were collected and fasting plasma glucose and lipids, blood pressure, and common carotid artery intima-median thickness (CCA-IMT) were measured. (1) Composition of the cases: 39.1% were non-smokers, 25.7% were former smokers and 35.2% were current smokers. The mean (95% confidence interval) carotid IMT was 0.78 (0.77 - 0.79) mm. 18.4% of the subjects had carotid IMT equal to or thicker than 1.0 mm while 34.1% had carotid plaque. (2) After adjusting for age, sex, physical activity, body mass index, fasting glucose, triglyceride, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, compared to never smokers, current smokers had significantly increased risk for thicker IMT and carotid plaque [odds ratio (OR) = 1.82, 95%CI: 1.30 - 2.55 and OR = 1.95, 95%CI: 1.38 - 2.75, respectively, all P < 0.001]. The risk for thicker IMT and carotid plaque increased with the increasing amount (cigarettes/day) and duration of smoking (years) as well with cigarette pack-years (P for trend all ≤ 0.01). An elevated risk with a clear dose-response relationship was found between cigarette smoking and carotid atherosclerosis. Quitting smoking or reducing the amount of smoking may lower the risk of atherosclerosis, preventing and controlling the occurrence of cardiovascular diseases, and reducing the related cardiovascular mortalities.


Usability of graphene oxide as a mycotoxin binder: In vitro study.
Mycotoxin management in agriculture is an essential challenge for maintaining the health of both animals and humans. Choosing the right adsorbent is still a question for many breeders and an important criterion for feed manufacturers. New adsorbents are still being sought. Graphene oxide is a promising material in the field of nanotechnology, which excels in its adsorption properties. Presented in vitro study investigates graphene oxide for the binding of mycotoxins from crushed wheat. The results show that graphene oxide has an adsorption capacity for aflatoxin 0.045 mg/g, zearalenone 0.53 mg/g and deoxynivalenol 1.69 mg/g at 37° C. In vitro simulation of crushed wheat digestion showed rapid adsorption during the gastric phase. Of the minerals, Mg, Cu and Zn were the most adsorbed. The applied dose of graphene oxide of 10 mg/g caused only a slight inhibition of the digestive enzymes α-amylase and trypsin compared to pepsin and gastric lipase. In vitro results indicated the suitability of graphene oxide in the adsorption of the aflatoxin, zearalenone and deoxynivalenol.


Comparison Of Early-Stage High-Grade Serous Primary Fallopian Tube Cancers and Epithelial Ovarian Cancers: A Multicenter Study.
We compared the disease free-survival (DFS) and overall survival (OS) rates of patients with high-grade serous primary fallopian tube cancer (HG-sPFTC) and high-grade serous epithelial ovarian cancer (HG-sEOC). 22 early-stage cancer patients (International Federation of Gynecology and Obstetrics (FIGO) stages I-II) with HG-sPFTC were retrospectively evaluated. In addition, 44 control patients diagnosed with HG-sEOC were matched to these patients with respect to tumor stage at diagnosis. All patients underwent complete surgical staging, followed by adjuvant chemotherapy. Kaplan-Meier curves were used to generate survival data. The mean age of HG-sPFTC patients was 59.4 ± 6.2 years, and that of HG-sEOC patients 55.2 ± 11.0 years (p = 0.002). All patients underwent 6 cycles of platinum-based adjuvant chemotherapy. All operations were optimal. The 5-year DFSs were 77.3% for HG-sPFTC patients and 75% for HG-sEOC patients (p = 1.00).The 5-year OS rates were 81.8% in women with HG-sPFTC and 77.3% in those with HG-sEOC (p = 0.75). The DFS and OS rates of patients with early-stage (FIGO stages I and II) HG-sPFTC and HG-sEOC were similar. The surgical and adjuvant therapy management of these malignancies should be similar.


Four closely related endornaviruses each with a low incidence in the phytopathogenic fungi Exserohilum turcicum or Bipolaris maydis.
Endornaviruses are known to occur widely in plants, fungi, and oomycetes, but our understanding of their diversity and distribution is limited. In this study, we report the discovery of four endornaviruses tentatively named Setosphaeria turcica endornavirus 1 (StEV1), Setosphaeria turcica endornavirus 2 (StEV2), Bipolaris maydis endornavirus 1 (BmEV1), and Bipolaris maydis endornavirus 2 (BmEV2). StEV1 and StEV2 infect Exserohilum turcicum, while BmEV1 and BmEV2 infect Bipolaris maydis. The four viruses encode a polyprotein with less than 40 % amino acid sequence identity to other known endornaviruses, indicating that they are novel, previously undescribed endornaviruses. However, StEV1 and BmEV1 share a sequence identity of 78 % at the full-genome level and 87 % at the polyprotein level, suggesting that they may belong to the same species. Our study also found that each of the four endornaviruses has an incidence of approximately 3.5 % to 5.5 % in E. turcicum or B. maydis. Interestingly, BmEV1 and BmEV2 were found to be unable to transmit between hosts of different vegetative incompatibility groups, which may explain their low incidence.


Accumulation of radioactive cesium released from Fukushima Daiichi Nuclear Power Plant in terrestrial cyanobacteria Nostoc commune.
The Fukushima Daiichi Nuclear Power Plant accident released large amounts of radioactive substances into the environment and contaminated the soil of Tohoku and Kanto districts in Japan. Removal of radioactive material from the environment is an urgent problem, and soil purification using plants is being considered. In this study, we investigated the ability of 12 seed plant species and a cyanobacterium to accumulate radioactive material. The plants did not accumulate radioactive material at high levels, but high accumulation was observed in the terrestrial cyanobacterium Nostoc commune. In Nihonmatsu City, Fukushima Prefecture, N. commune accumulated 415,000 Bq/kg dry weight (134)Cs and 607,000 Bq kg(-1) dry weight (137)Cs. The concentration of cesium in N. commune tended to be high in areas where soil radioactivity was high. A cultivation experiment confirmed that N. commune absorbed radioactive cesium from polluted soil. These data demonstrated that radiological absorption using N. commune might be suitable for decontaminating polluted soil.


Individual music therapy for managing neuropsychiatric symptoms for people with dementia and their carers: a cluster randomised controlled feasibility study.
Previous research highlights the importance of staff involvement in psychosocial interventions targeting neuropsychiatric symptoms of dementia. Music therapy has shown potential effects, but it is not clear how this intervention can be programmed to involve care staff within the delivery of patients' care. This study reports initial feasibility and outcomes from a five month music therapy programme including weekly individual active music therapy for people with dementia and weekly post-therapy video presentations for their carers in care homes. 17 care home residents and 10 care staff were randomised to the music therapy intervention group or standard care control group. The cluster randomised, controlled trial included baseline, 3-month, 5-month and post-intervention 7-month measures of residents' symptoms and well-being. Carer-resident interactions were also assessed. Feasibility was based on carers' feedback through semi-structured interviews, programme evaluations and track records of the study. The music therapy programme appeared to be a practicable and acceptable intervention for care home residents and staff in managing dementia symptoms. Recruitment and retention data indicated feasibility but also challenges. Preliminary outcomes indicated differences in symptoms (13.42, 95 % CI: [4.78 to 22.07; p = 0.006]) and in levels of wellbeing (-0.74, 95 % CI: [-1.15 to -0.33; p = 0.003]) between the two groups, indicating that residents receiving music therapy improved. Staff in the intervention group reported enhanced caregiving techniques as a result of the programme. The data supports the value of developing a music therapy programme involving weekly active individual music therapy sessions and music therapist-carer communication. The intervention is feasible with modifications in a more rigorous evaluation of a larger sample size. Clinicaltrials.gov, number NCT01744600.


Systemic vasculopathy with altered vasoreactivity in a transgenic mouse model of scleroderma.
Vasculopathy, including altered vasoreactivity and abnormal large vessel biomechanics, is a hallmark of systemic sclerosis (SSc). However, the pathogenic link with other aspects of the disease is less clear. To assess the potential role of transforming growth factor beta (TGF-beta) overactivity in driving these cardiovascular abnormalities, we studied a novel transgenic mouse model characterized by ligand-dependent activation of TGF-beta signaling in fibroblasts. The transgenic mouse strain Tbeta RIIDeltak-fib is characterized by balanced ligand-dependent upregulation of TGF-beta signaling. Aortic and cardiac tissues were examined with histologic, biochemical, and isolated organ bath studies. Vascular and perivascular architecture was examined by hematoxylin and eosin (H&E) and special stains including immunostaining for TGF-beta1 and phospho-Smad2/3 (pSmad2/3). Confirmatory aortic smooth muscle cell proliferation, phenotype, and functional assays, including signaling responses to exogenous TGF-beta and endothelin-1, were performed. Aortic ring contractile responses to direct and receptor-mediated stimulation were assessed. Aortic ring contractility and relaxation were diminished compared with wild-type controls, and this was associated with aortic adventitial fibrosis confirmed histologically and with Sircol assay. TGF-beta1 and pSmad 2/3 expression was increased in the adventitia and smooth muscle layer of the aorta. Aortic smooth muscle cells from transgenic animals showed significant upregulation of TGF-beta- responsive genes important for cytoskeletal function, such as transgelin and smoothelin, which were then resistant to further stimulation with exogenous TGF-beta1. These cells promoted significantly more contraction of free floating type I collagen lattices when compared with the wild-type, but were again resistant to exogenous TGF-beta1 stimulation. Aortic ring responses to receptor-mediated contraction were reduced in the transgenic animals. Specifically, bosentan reduced endothelin-mediated contraction in wild-type animals, but had no effect in transgenic animals, and endothelin axis gene expression was altered in transgenic animals. Transgenic mice developed cardiac fibrosis. The histologic, biochemical, and functional phenotype of this transgenic mouse model of scleroderma offers insight into the altered biomechanical properties previously reported for large elastic arteries in human SSc and suggests a role for perturbed TGF-beta and endothelin activity in this process.


Explanations of risk in families without identified mutations for hereditary nonpolyposis colorectal cancer.
Genetic testing for hereditary forms of cancer does not always identify a causative mutation. Little is known about personal or family response to these indeterminate results when a hereditary form of cancer is suspected. This study explored thoughts about and responses to risk for hereditary nonpolyposis colorectal cancer (HNPCC) when a family member has received indeterminate genetic test results. In this qualitative study, data were gathered from index cases who received indeterminate genetic test results through a longitudinal study offering genetic counseling and testing for HNPCC. First-degree relatives of these indeterminate index cases were also invited to participate in the qualitative interview. Semistructured telephone interviews were conducted with index cases and their at-risk first-degree relatives. Data were analyzed using the within- and across-case method. The across-case analysis led to the development of the Awareness and Surveillance Trajectory, which describes individual interpretations of and responses to risk, based on personal and family history. Explanations of risk addressed the meaning of cancer in the family and provided context for individual interpretations. They were identified using within-case analysis and organized into a typology: innate, exceptional, idiosyncratic, and undeveloped explanations. Members of families without identified HNPCC mutations vary in their explanations for, interpretations of, and responses to indeterminate genetic test results. Explanations of family risk and interpretations of individual risk offer healthcare providers valuable information. In combination with the Awareness and Surveillance Trajectory, assessment of these beliefs can facilitate development of individualized recommendations and strategies for possible preventive actions.


Validity of Broselow tape for estimating weight of Indian children.
The Broselow tape has been validated in both ambulatory and simulated emergency situations in the United States and is believed to reduce complications arising from inaccurate drug dosing and equipment sizing in paediatric population. This study was conducted to determine the relationship between the actual weight and weight determined by Broselow tape in the Indian children and to derive an equation for determination of weight based on height in the Indian children. This cross-sectional study was conducted at a tertiary care hospital in Mumbai, India. The participants' weights were divided into three groups <10 kg, 10-18 kg and >18 kg with a total sample size estimated to be 210 (70 in each group). Using the tape, the measured weight was compared to Broselow-predicted weight and percentage weight was calculated. Accuracy was defined as agreement on Broselow colour-coded zones, as well as agreement within 10 per cent between the measured and Broselow-predicted weights. The resulting data were compared with weights estimated by advanced paediatric life support (APLS) and updated APLS formulae using Pearson's correlation coefficient. The mean percentage differences were -11.78, -17.09 and -14.27 per cent for <10, 10-18 and >18 kg weight-based groups, respectively. The Broselow colour-coded zone agreement was 33.3 per cent in children weighing <10 kg, but only 7.4 per cent in the 10-18 kg group and 33.9 per cent in the >18 kg group. Agreement within 10 per cent was 53.13 per cent for the <10 kg group, but only 21.08 per cent for the 10-18 kg group and 33.9 per cent for the >18 kg group. Application of 10 per cent weight correction factor improved the percentages to 79.2 per cent for the <10 kg category, to 55.70 per cent for the 10-18 kg group and to 61.0 per cent for the >18 kg group. The correlation coefficient between actual weight and weights estimated by Broselow tape (r=0.89) was higher than that between actual weight and weight estimated by APLS method or updated APLS formulae (r=0.68) in 12-60 months age group as well as in >60 months age group (r=0.76). Broselow weight overestimated weight by >10 per cent in majority of Indian children. The weight overestimation was greater in children belonging to over 18 and 10-18 kg weight groups. Applying 10 per cent weight correction factor to the Broselow-predicted weight may provide a more accurate estimation of actual weight in children attending public hospital. Weights estimated using Broselow tape correlated better with actual weights than those calculated using APLS and updated APLS formulae.


Femtosecond laser machining for characterization of local mechanical properties of biomaterials: a case study on wood.
The standard preparation technique for micro-sized samples is focused ion beam milling, most frequently using Ga+ ions. The main drawbacks are the required processing time and the possibility and risks of ion implantation. In contrast, ultrashort pulsed laser ablation can process any type of material with ideally negligible damage to the surrounding volume and provides 4 to 6 orders of magnitude higher ablation rates than the ion beam technique. In this work, a femtosecond laser was used to prepare wood samples from spruce for mechanical testing at the micrometre level. After optimization of the different laser parameters, tensile and compressive specimens were produced from microtomed radial-tangential and longitudinal-tangential sections. Additionally, laser-processed samples were exposed to an electron beam prior to testing to study possible beam damage. The specimens originating from these different preparation conditions were mechanically tested. Advantages and limitations of the femtosecond laser preparation technique and the deformation and fracture behaviour of the samples are discussed. The results prove that femtosecond laser processing is a fast and precise preparation technique, which enables the fabrication of pristine biological samples with dimensions at the microscale.


Transformation of Xylella fastidiosa with broad host range RSF1010 derivative plasmids.
SUMMARY The Gram-negative, fastidious bacterium Xylella fastidiosa was successfully transformed with two RSF1010 derivative plasmids belonging to the incompatibility group IncQ, using electroporation. These two derivative plasmids, pXF004 and pXF005, were found to be present as autonomous, structurally unchanged DNA molecules when propagated in X. fastidiosa. However, neither pXF004 nor pXF005 were stably maintained in X. fastidiosa without antibiotic selection. When plasmid DNAs were isolated from X. fastidiosa, or plasmid DNAs isolated from E. coli were supplemented with a TypeOne inhibitor, TRI, the frequency of transformation was increased by 13- or 5-fold, respectively. Plasmid pXF005 was also used to transform one additional grapevine strain of X. fastidiosa.


GenoType MTBDRsl for molecular detection of second-line-drug and ethambutol resistance in Mycobacterium tuberculosis strains and clinical samples.
The purpose of this study was to evaluate the GenoType MTBDRsl assay (Hain Lifescience GmbH, Nehren, Germany) for its ability to detect resistance to fluoroquinolones (FLQ), injectable second-line antibiotics [kanamycin (KM) and capreomycin (CM)], and ethambutol (EMB) in Mycobacterium tuberculosis clinical strains and directly in clinical samples. A total of 34 clinical strains were characterized with the Bactec 460 TB system. Fifty-four clinical samples from 16 patients (5 were smear negative and 49 were smear positive) were also tested directly. The corresponding isolates of the clinical specimens were also analyzed with the Bactec 460TB. When there was a discrepancy between assays, pyrosequencing was performed. The overall rates of concordance of the MTBDRsl and the Bactec 460TB for the detection of FLQ, KM/CM, and EMB susceptibility in clinical strains were 72.4% (21/29), 88.8% (24/27), and 67.6% (23/34), whereas for clinical samples, rates were 86.5% (45/52), 92.3% (48/52), and 56% (28/50), respectively. In conclusion, the GenoType MTBDRsl assay may be a useful tool for making early decisions regarding KM/CM susceptibility and to a lesser extent regarding FLQ and EMB susceptibility. The test is able to detect mutations in both clinical strains and samples with a short turnaround time. However, for correct management of patients with extensively drug-resistant tuberculosis, results must be confirmed by a phenotypical method.


Experimental observation of nanophase segregation in aqueous salt solutions around the predicted liquid-liquid transition in water.
The liquid-liquid transition in supercooled liquid water, predicted to occur around 220 K, is controversial due to the difficulty of studying it caused by competition from ice crystallization (the so-called "no man's land"). In aqueous solutions, it has been predicted to give rise to phase separation on a nanometer scale between a solute-rich high-density phase and a water-rich low-density phase. Here we report direct experimental evidence for the formation of a nanosegregated phase in eutectic aqueous solutions of LiCl and LiSCN where the presence of crystalline water can be experimentally excluded. Femtosecond infrared and Raman spectroscopies are used to determine the temperature-dependent structuring of water, the solvation of the SCN- anion, and the size of the phase segregated domains.


The RsaI polymorphism in the alpha-fibrinogen gene and response of plasma fibrinogen to physical training--a controlled randomised clinical trial in men.
We have previously reported cross-sectional data on an interaction effect between physical activity and alpha-fibrinogen RsaI polymorphism on fibrinogen in postmenopausal women. In the present controlled randomised study, we investigated the role of the RsaI polymorphism in determining the response of fibrinogen to long-term regular exercise. Middle-aged men (n = 140), randomly selected from the population registry, were randomised into an exercise or a reference group for a 3-year low intensity exercise intervention. Complete data were available in 125 men. The RsaI restriction enzyme detects threonine (Thr) to alanine change in the fibrinogen alpha codon 312. Anaerobic ventilatory threshold increased by 4%, but decreased by 2% in the exercise and reference groups, respectively. Mean fibrinogen did not decrease in either study group. However, in the exercise group, individual changes in anaerobic threshold explained 48% of the variance in fibrinogen changes in the Thr homozygotes. Our data offer a new aspect of beneficial effects of regular physical exercise on risk factors for coronary heart disease.


Consistency of interictal and ictal onset localization using magnetoencephalography in patients with partial epilepsy.
The aim of this study was to evaluate the spatial accuracy of interictal magnetoencephalography (MEG) in localizing the primary epileptogenic focus in comparison with alternative MEG-derived estimates such as ictal onset recording or sensory mapping of the periphery where seizures manifest. During this retrospective study of 12 patients with epilepsy who had undergone successful magnetic source (MS) imaging with the aid of a dual 37-channel biomagnetometer as well as simultaneous MEG/electroencephalography (EEG) recordings, ictal events were observed in five patients and quantitative comparisons of interictal spike and ictal seizure onset source localizations were made. In the eight patients who had presented with sensorimotor seizure, source localization of cortical sites concordant with seizure foci was determined using somatosensory functional mapping, and the results were quantitatively compared with interictal spike source localizations. Interictal spike sources demonstrated on MEG localized to the same region as the corresponding ictal event or somatosensory source localizations. The mean distance between the ictal foci and interictal spike sources was 1.1 +/- 0.3 cm. Results of functional somatosensory mapping in patients with sensorimotor seizures demonstrated that seizure sources consistently colocalized with interictal MEG spike sources, with a mean distance of 1.5 +/- 0.4 cm. No systematic directional bias was observed. Interictal sources tended to be tightly clustered, and the mean ellipsoid volume, defined by one standard deviation of the source spatial coordinates, was 1 cm3. Interictal spike localizations on MEG were concordant with ictal and, where relevant, functional somatosensory mapping localizations. These findings support the interpretation of interictal spikes on MEG as a useful and effective noninvasive method for localizing primary seizure foci.


Orthostatic hypotension in de novo Parkinson disease.
It is accepted that orthostatic hypotension is a clinical marker for the diagnosis of multiple system atrophy, but conflicting data indicate that it may also be present in Parkinson disease (PD). To evaluate the prevalence of autonomic cardiovascular impairment and orthostatic hypotension in a large group of patients with de novo PD, followed up for at least 7 years, to clinically confirm the diagnosis of the disease. During a 2-year recruiting period, 60 untreated patients diagnosed as having idiopathic PD underwent autonomic cardiovascular function evaluation using the Ewing test. Patients subsequently received dopaminergic therapy and their condition was followed up for at least 7 years. Nine (15%) of 60 patients were excluded from the study because during the follow-up period a parkinsonian syndrome was diagnosed (5 had multiple system atrophy and 4 had progressive supranuclear palsy). Data from 51 patients with PD underwent final statistical analysis and the results were compared with those of 51 age-matched healthy control subjects who had taken the same battery of autonomic tests. A statistically significant difference was found in postural hypotension (P =.02) and deep breathing test results (P =.03) between patients and controls. Seven (14%) of 51 patients with PD and 3 (60%) of 5 patients with multiple system atrophy had a decrease of more than 20 mm Hg in systolic blood pressure on standing. Data from this study indicate a high prevalence of sympathetic and parasympathetic failure in patients with de novo PD, and when using a decrease of at least 20 mm Hg in systolic blood pressure, manometric orthostatic hypotension was found in 7 (14%) of the 51 patients with de novo PD.


A calculated response: control of inflammation by the innate immune system.
Inflammation is a rapid yet coordinated response that can lead to the destruction of microbes and host tissue. Triggers capable of inducing an inflammatory response include tissue damage and infection by pathogenic and nonpathogenic microbes. Each of these triggers represents a qualitatively distinct stress to the host immune system, yet our understanding of whether they are interpreted as such remains poor. Accumulating evidence suggests that recognition of these distinct stimuli converges on many of the same receptors of the innate immune system. Here I provide an overview of these innate receptors and suggest that the innate immune system can interpret the context of an inflammatory trigger and direct inflammation accordingly.


Cyclooxygenase-2 inhibition and side-effects of non-steroidal anti-inflammatory drugs in the gastrointestinal tract.
Inhibition of prostaglandin biosynthesis via inhibition of the fatty acid cyclooxygenase (COX) is the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs). This results in an inhibition of the inflammatory and pain-producing activities of prostaglandins at a site of tissue injury but also in inhibition of prostaglandin production in the gastrointestinal tract (GI) and platelets, i.e. sites where endogenous prostaglandins are possibly involved in control of physiological functions. The discovery of two COX isoenzymes, COX-1 and COX-2, and the detection of their separate function and regulation, has initiated the search for new and putatively more selective inhibitors of prostaglandin biosynthesis. Specifically, selective inhibitors of COX-2 were developed in order to improve the anti-inflammatory and analgetic specificity and potency of the compounds and to reduce side-effects in the GI tract. Available experimental and clinical data of selective COX-2 inhibitors, including flosulide, celecoxib or rofecoxib, suggest improved gastric tolerance as compared to conventional, non-selective NSAIDs. However, experimental evidence suggests that both, the analgetic and anti-inflammatory action of COX-inhibitors, might also require inhibition of COX-1. COX-2-selective compounds at anti-inflammatory doses might have other side-effects, and for example reduce vascular prostacyclin production. Evidence is accumulating that COX-2 might not only be considered as a putatively detrimental enzyme but rather a highly regulated enzyme that also contributes to tissue protection and is even constitutively expressed in healthy human stomach mucosa. This paper reviews some of these newer aspects of COX-2-selective inhibitors in clinical use and discusses their possible benefits and risks.


A stimuli-responsive and chemically tunable organic microcrystal laser switch.
We demonstrated a stimuli-responsive and chemically switchable organic microbelt laser through reversible protonation-deprotonation reactions. The parent microbelt cavity together with the optically allowed 0-1 transition of H-aggregates enables a microlaser to operate at 585 nm. Upon HCl vapor treatment, the protonation of surface molecules shifts the lasing wavelength to 560 nm, generating an intensity contrast ratio >105, accompanied by a sharp color change from orange (deprotonated) to green (protonated). When treated with HCl-NH3 vapor, the protonation-deprotonation reactions lead to a reversible microlaser switch between 585 nm and 560 nm with good reproducibility and photostablity, making them attractive in high-throughput chemical and biological sensing applications.


Synthesis, structure and antifungal activity of thiophene-2,3-dicarboxaldehyde bis(thiosemicarbazone) and nickel(II), copper(II) and cadmium(II) complexes: unsymmetrical coordination mode of nickel complex.
The reaction of nickel(II), copper(II) chlorides and cadmium(II) chloride and bromide with thiophene-2,3-dicarboxaldehyde bis(thiosemicarbazone) (2,3BTSTCH2) leads to a series of new complexes: [Ni(2,3BTSTCH)]Cl, [Cu(2,3BTSTC)], [CdCl2(2,3BTSTCH2)] and [CdBr2(2,3BTSTCH2)]. The crystal structures of the ligand and of [Ni(2,3BTSTCH)]Cl complex have been determined. In this case, we remark an unusual non-symmetrical coordination mode for the two functional groups: one acting as a thione and the second as a deprotonated thiolate. All compounds have been tested for their antifungal activity against human pathogenic fungi: Candida albicans, Candida glabrata and Aspergillus fumigatus, the cadmium complexes exhibit the highest antifungal activity. Cytotoxicity was evaluated using two biological methods: human MRC5 cultured cells and brine shrimp Artemia salina bioassay.


A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Brain damage among the prenatally exposed.
Significant effects on the developing brain of exposure to ionizing radiation are seen among those individuals exposed in the 8th through the 25th week after fertilization. These effects, particularly in the most sensitive period, 8-15 weeks after fertilization, manifest themselves as an increased frequency of severe mental retardation (SMR), a diminution in IQ score and in school performance, and an increase in the occurrence of seizures. Of 30 SMR cases, 18 (60%) had small heads. About 10% of the individuals with small head sizes observed among the in utero clinical sample were mentally retarded. When all of the cases of mental retardation are included in the analysis, a linear dose-response model fits the data adequately and no evidence of a threshold emerges; however, if the two probable nonradiation-related cases of Down's syndrome are excluded from the 19 SMR cases exposed 8-15 weeks after fertilization, the evidence of a threshold is stronger. The 95% lower bound of the threshold based on the new dosimetry system appears to be in the range of 0.12-0.23 Gy. In the 16-25 week period, the 95% lower bound of the threshold is 0.21 Gy both with and without inclusion of two probable nonradiation-related retarded cases. In a regression analysis of IQ scores and school performance data, a greater linearity is suggested with the new dosimetry (DS86) than with the old (T65DR), but the mean IQ score and the mean school performance of those exposed in utero to doses under 0.10 Gy are similar, and not statistically different from the means in the control group. The risk ratios for unprovoked seizures, following exposure during the 8th through the 15th week after fertilization, are 4.4 (90% confidence interval: 0.5-40.9) after 0.10-0.49 Gy and 24.9 (4.1-191.6) after 0.50 Gy or more when the mentally retarded are included and 4.4 (0.5-40.9) and 14.5 (0.4-199.6), respectively, when they are excluded.


A systematic review and meta-analysis of micronutrient intakes during pregnancy in developed countries.
Micronutrient status during pregnancy influences maternal and fetal health, birth outcomes, and the risk of chronic disease in offspring. Research reporting dietary intake during pregnancy in nationally representative population samples, however, is limited. This review summarizes the micronutrient intakes of pregnant women from developed countries and compares them with relevant national recommendations. A systematic search without date limits was conducted. All studies reporting the micronutrient intakes of pregnant women were considered, irrespective of design. Two authors independently identified studies for inclusion and assessed methodological quality. Nutritional adequacy was summarized, with confounding factors considered. Meta-analysis data are reported for developed countries collectively, by geographical region, and by dietary methodology. Pregnant women in developed countries are at risk of suboptimal micronutrient intakes. Folate, iron, and vitamin D intakes were consistently below nutrient recommendations in each geographical region, and calcium intakes in Japan were below the Japanese recommendations and the average intake levels in other developed countries. Research examining the implications of potential nutrient insufficiency on maternal and offspring health outcomes is needed along with improvements in the quality of dietary intake reporting.


Functional responses in animal movement explain spatial heterogeneity in animal-habitat relationships.
Understanding why heterogeneity exists in animal-habitat spatial relationships is critical for identifying the drivers of animal distributions. Functional responses in habitat selection - whereby animals adjust their habitat selection depending on habitat availability - are useful for describing animal-habitat spatial heterogeneity. However, they could be yielded by different movement tactics, involving contrasting interspecific interactions. Identifying functional responses in animal movement, rather than in emergent spatial patterns like habitat selection, could disentangle the effects of different movement behaviours on spatial heterogeneity in animal-habitat relationships. This would clarify how functional responses in habitat selection emerge and provide a general tool for understanding the mechanistic drivers of animal distributions. We tested this approach using data from GPS-collared woodland caribou (Rangifer tarandus), a prey species under top-down control. We tested how caribou selected and moved with respect to a key resource (lichen-conifer stands) as a function of the availability of surrounding refuge land-cover (closed-conifer stands), using step selection functions. Caribou selected resource patches more strongly in areas richer in refuge land-cover - a functional response in habitat selection. However, adjustments in multiple movement behaviours could have generated this pattern: stronger directed movement towards resource patches and/or longer residency within resource patches, in areas richer in refuges. Different contributions of these behaviours would produce contrasting forager spatial dynamics. We identified functional responses in both movement behaviours: caribou were more likely to move towards resource patches in areas richer in refuge land-cover, and to remain in these patches during movement steps. This tactic enables caribou to forage for longer in safer areas where they can rapidly seek refuge in dense cover when predators are detected. Our study shows that functional responses in movement can expose the context-dependent movement decisions that generate heterogeneity in animal-habitat spatial relationships. We used these functional responses to characterise anti-predator movement tactics employed by a large herbivore, but they could be applied in many different scenarios. The movement rules from functional responses in movement are well-suited to integration in spatial explicit individual-based models for forecasting animal distributions in landscapes undergoing environmental change.


[Volume transmission as a means of interneuronal interaction in the striatum].
This review of literature and own data is devoted to a special mode of intercellular communication in the GNS--volume transmission, that is based on diffusion of neuromediators from points of release through the brain extracellular space to distant non-synaptic receptor sites. Using the main neurotransmitters of the striatum (dopamine, glutamate and GABA) as an example, the author has analysed the evidence for the existence of volume transmission in this brain region, the tentative mechanisms underlying this mode for information processing, and receptors involved. Much attention has been paid to functional significance of volume transmission in the striatum for maintenance of behaviour, operated by this brain area.


Lateral reflections are favorable in concert halls due to binaural loudness.
A recent study on perceptual difference in simulated concert halls showed that a concert hall renders stronger sound with more bass when the temporal envelope of a signal is preserved in the reflections [Lokki et al., J. Acoust. Soc. Am. 129, EL223-EL228 (2011)]. In the same study the lateral reflections were shown to contribute to the perceived envelopment and openness. Moreover, the listening test results suggest that lateral reflections contribute to perception of sound source distance. Here, it is shown that lateral reflections are beneficial due to their increasing effect on binaural loudness-the phenomenon known well in psychoacoustics, but not in architectural acoustics. The reflections from the side are amplified more than median plane reflections, in particular at high frequencies, due to the shape of the human head.


[Morphological evaluation of toxic effect of kartolin-2].
Lipid dystrophy, rapid reduction of RNA and glycogen content in the liver of all experimental rats, developing as a result of acute kartolin-2 poisoning testify to an expressed hepatotropic effect of the substance. Alongside with the processes of parenchymal liver cell damage the signs of intracellular regenerating processes--increase of the size of hepatocytes nuclei are detected. Liver protein metabolism disturbances are observed following exposure to kartolin-2 in the acute experiment. Chronic exposure to kartolin-2, and, specifically to its preparation form in the dose 1/100 LD50 cause lipid infiltration, reduction of histochemical indicators of liver glycogen, and RNA content. No-effect doses of kartolin-2 have been determined.


Recent advances in head and neck cancer therapy: the role of new cytotoxic and molecular-targeted agents.
To provide an update on novel compounds in head and neck cancer (HNC) therapy, with emphasis on biologic agents. Cisplatin-5-fluorouracil (5-FU) is the standard chemotherapeutic approach in HNC. Strategies to improve its activity include the substitution of 5-FU with oral fluoropyrimidines; the substitution of cisplatin with different analogs or formulations; and the use of additional or alternative compounds. Epidermal growth factor receptor (EGFR) is the most appealing target for novel therapies in HNC. Cetuximab, a chimeric anti-EGFR monoclonal antibody, has undergone evaluation in platinum-refractory recurrent or metastatic HNC with a satisfactory and consistent response rate (10-13%) across three different Phase II studies in association with platinum or as single agent. A recent Phase III placebo-controlled trial has shown better response rate for patients treated with cetuximab and cisplatin, with respect to those treated with cisplatin alone. EGFR tyrosine kinase inhibitors (TKIs) are under investigation in HNC, and efforts are made to understand which molecular features are associated with objective responses. One appealing way to use EGFR TKIs is in combination with other biologic compounds, such as anti-angiogenic agents. New molecular-targeted therapies are inducing consistent, small improvements in HNC management. The major challenge regards how to better combine them with the final aim of obtaining long-term stabilization of advanced disease.


Phytochemical and Psychotropic Research of Motherwort (Leonurus cardiaca L.) Modified Dry Extracts.
The prospect of creating a new medicine with psychotropic activity is shown as a result of studying the chemical composition and pharmacological activity of modified dry extracts of motherwort (Leonurus cardiaca L.) tincture. The most promising substances were the dry extracts, modified by adding small amounts of arginine, valine, phenylalanine, glycine, lysine, and alanine. A total of 15 main phenolic substances were found in the extracts, and eight of them were identified. There were also 10 hydroxycinnamic acids in these extracts, three of which were identified (chlorogenic, caffeic, and rosmarinic acids). The dominant hydroxycinnamic acids were chlorogenic and caffeic acids. Among flavonoids, catechin, hyperoside, and rutin were identified. It should be noted that the extracts had a significant content of ellagic acid. On the basis of the results of the phytochemical analysis of the extracts, it can be concluded that the composition of phenolic compounds does not differ significantly, and the main differences are related to amino acids, which obviously have an impact on the overall pharmacological effect. The results obtained indicate the presence of anxiolytic activity in the motherwort extracts studied in complex with amino acids. The extracts with glycine, valine, and arginine were more effective in reducing anxiety in animals.